On the Mechanism of the Reactivity of 1,3-Dialkylimidazolium Salts under Basic to Acidic Conditions: A Combined Kinetic and Computational Study

Article abstract of DOI:10.1002/anie.201805016

Comprehensive spectroscopic kinetic studies illustrate an alternative mechanism for the traditional free-carbene intermediated H/D exchange reaction of 1,3-dialkylimidazolium salts under neutral (D₂O) and acidic conditions (DCl/D₂O 35 wt % solution). The deuteration of high purity [bmim]Cl in D₂O is studied at different temperatures, in absence of catalyst or impurities, to yield an activation energy. DFT transition-state modelling, of a small water cluster and [bmim] cation, also yields an activation energy which strongly supports the proposed mechanism. The presence of basic impurities are shown to significantly enhance the exchange reaction, which brings into question the need for further analysis of technical purities of ionic liquids and the implications for a wide range of chemical reactions in such media.

Full text of DOI:10.1002/anie.201805016

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Accepted Article
Title: On the mechanism of the reactivity of 1,3-dialkylimidazolium
salts under basic to acidic conditions: a combined kinetic and
computational study.
Authors: Daniel Rico del Cerro, Raúl Mera Adasme, Alistair William
Thomas King, Jesus Enrique Perea Buceta, Sami Heikkinen,
Tapio Hase, Dage Sundholm, and Kristiina Wähälä
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201805016
Angew. Chem. 10.1002/ange.201805016
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Angewandte Chemie International Edition
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On the mechanism of the reactivity of 1,3-dialkylimidazolium salts
under basic to acidic conditions: a combined kinetic and
computational study.
[
a]
[b]
[a]
[a]
Daniel Rico del Cerro,* Raúl Mera-Adasme,* Alistair W. T. King, Jesus E. Perea-Buceta, Sami
[
a]
[a]
[a]
[a], [c]
Heikkinen, Tapio Hase, Dage Sundholm,* and Kristiina Wähälä.
Abstract: Comprehensive spectroscopic kinetic studies illustrate an
alternative mechanism for the traditional free-carbene intermediated
H/D exchange reaction of 1,3-dialkylimidazolium salts under neutral
A particular well-known application of NHCs are H/D exchange
processes, which constitute an essential diagnostic tool to gain
mechanistic insight into a myriad of chemical and biological
processes.[ This also allows access to isotopically labelled
compounds with interesting pharmaceutical profiles[7] or
perdeuterated solvents for analytics,[8] among many other
6]
(
D
2
O) and acidic conditions (DCl/D
2
O 35 wt % solution). The
O is studied at different
deuteration of high purity [bmim]Cl in D
2
temperatures, in absence of catalyst or impurities, to yield an
activation energy. DFT transition-state modelling, of a small water
cluster and [bmim] cation, also yields an activation energy which
strongly supports the proposed mechanism. The presence of basic
impurities are shown to significantly enhance the exchange reaction,
which brings into question the need for further analysis of technical
purities of ionic liquids and the implications for a wide range of
chemical reactions in such media.
applications.
1,3-Dialkylimidazolium
salts
also
exhibit
considerable advantages to participate in neutral H/D-exchange
processes that enable the use of the sustainable and cost-
effective deuterium oxide, as deuterium source. Indeed, the
structural versatility of these salts allows tailoring at will their acid-
base properties to facilitate such isotopic exchange processes.[
9]
It is well-known that the proton at the C2 position of the
imidazolium ring is labile enough[10] to undergo deprotonation,
upon strong or mild basic conditions to generate imidazole-2-
In the last decades, there are indications that some of the more
basic 1,3-dialkylimidazolium ionic liquids, 1, are ‘non-innocent’, as
reaction media.[1] This has been attributed to the basicity of the
anion counterpart,[2] but is also dependent on the acidity of the
cation at the C2 position of the imidazolium ring.[3] The acidic
nature of 1,3-dialkylimidazolium ionic liquids 1, has also been a
versatile source for the facile generation of N-heterocyclic
carbenes (NHCs), with an extensive range of synthetic and
catalytic applications.[4]
ylidene species,[4, 5] that can further react with D O[11] (Scheme 1,
2
up). Surprisingly, only a few isolated examples have been
reported of such isotopic exchange processes proceeding upon
neutral conditions, none of which provide solid mechanistic insight
into the reactivity.[12] Only recently, Gehrke and Hollóczki
illustrated computationally that the ‘free-carbene’ species are not
necessarily involved in organocatalytic processes, with simple
[13]
aldehyde substrates.
Mechanistically, the traditional ‘free-carbene’ pathway involves
the formation of a covalent bond between the intermediate NHC
and a suitable substrate, after deprotonation of the NHC precursor
Herein, we present an experimental and computational study that
renders a concise mechanistic rationale for the H/D exchange at
(
1), using strong or mild basic conditions.[5]
[
a]
b]
c]
M. Sc. D. Rico del Cerro, Dr. A. W. T. King, Dr. J. E. Perea-Buceta,
Dr. S. Heikkinen, Prof. T. Hase, Prof. D. Sundholm.
Department of Chemistry.
University of Helsinki.
P.O. Box 55, A.I. Virtasen aukio 1, FIN-00014, Helsinki, Finland.
daniel.ricodelcerro@helsinki.fi
sundholm@chem.helsinki.fi
Prof. R. Mera-Adasme.
[
[
Departamento de Ciencias del Ambiente. Facultad de Química y
Biología.
Universidad de Santiago de Chile.
Av. Libertador Bernardo O’Higgins 3363, 9170022 Estacion Central,
Chile.
raul.mera@usach.cl
Prof. K. Wähälä.
Department of Biochemistry and Development Biology.
University of Helsinki.
Haartmaninkatu 3, P.O. Box 21, FI-000140, Helsinki, Finland.
Scheme 1. Reported mechanism under basic conditions and mechanism
proposed in this work under neutral and acidic conditions. Dotted lines in 6,
denote bonds which are broken and formed simultaneously.
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
the C2 position of imidazolium ionic liquids under neutral
conditions. A concerted ‘carbene-free’ mechanism is proposed
state structures. The Hessian matrices were employed to
calculate thermal corrections for the energies under the harmonic
approximation. The COSMO solvation model[ (=80 for water)
was applied, effectively charge-shielding the cationic charge but
not offering any species with significant dynamically restricted
Lewis basicity, in the absence of the explicit chloride anion. Thus,
the obtained activation free energy should represent a value as
20]
(
Scheme 1, bottom). These studies are not only consistent with
but also complement the mechanistic scenario, initially proposed
by Gehrke and Hollóczki,[13] for the conjugation with aldehydes.
To begin our studies, we selected chloride as the counter anion,
since it is reported that its reduced basicity prevents it from
reacting with reducing ends in cellulose, as opposed to the
acetate which does allow for this reaction to occur.[14] 1-butyl-3-
methylimidazolium chloride ([bmim]Cl), 2, was prepared
a
close to ‘neutral’ conditions as possible. The calculated ΔG for
the H/D exchange was 31.3 kcal/mol at 310 K, compared to the
experimental value of 31.1 kcal/mol.[21-22] The transition-state
geometry is shown in Figure 3, where a concerted proton
exchange occurs, mediated by H-bound water molecules.
[
15]
according to a modified literature procedure to very high purity
supporting information).
(
The H/D exchange under neutral conditions was investigated, by
1
H NMR (change in normalized relative intensities for C2-H), in
the temperature range of 300.25 K to 339.45 K (Figure 2). The
natural logarithmic plots yielded the rate constants (supporting
information Figures S6-S10). The Arrhenius plots (natural
logarithmic plot versus the inverse of temperature) gives a linear
trend, as shown in Figure 2 (inset), from which the activation
energy (E ) for the H/D conversion is obtained. Using the
a
Arrhenius equation [Eq. (1)] (where A is a pre-exponential factor
and R is the ideal gas constant) an experimental value of 31.1
kcal/mol was obtained for E
a
.
Figure 3. The geometry of the optimized transition state for the reaction in study,
modelled as a proton exchange. The leaving proton is at the bottom. Distances
shown in Å, correspond to H-bond distances.
k=Ae-Ea/RT
(1)
The kinetic data for H/D conversion of 2 under different
environments, such as neutral (D
solution) and basic conditions (sodium deuteroxide solution
NaOD 40 wt. %), triethylamine (Et N) or 1-methylimidazole (1-
2 2
O), acidic (DCl/D O 35 wt. %
(
3
MeIm)), are reported in Table 1. For comparison of deuteration
kinetics for imidazolium ionic liquids containing chloride vs the
more basic acetate anion, high purity 3-butyl-1methylimidazolium
acetate ([bmim][OAc]), 3, was prepared and the deuteration
kinetics reported in Table 1 for one temperature under neutral
conditions.
In the case of 2, a long reaction time and heating are needed to
reach a good yield in C2 H/D exchange under neutral conditions
(
Experiment 2, Table 1), whereas, deuterium incorporation at C2
in 3 is complete at room temperature after 4.8 hours (Experiment
1, Table 1). The differences in reactivity are assumed to be
related to the basicity of the counter anions.[2] Acetate anion is
more basic than chloride, therefore it has an enhanced catalytic
effect.
Figure 2. Initial 1st order kinetics, as a function of temperature for C2-H
deuteration, in excess of D O, leading to an Arrhenius plot (inset).
2
The reaction was also investigated computationally using DFT
transition-state modelling. This was achieved by carrying out
relaxed potential-energy surface scans (TPSS density
The catalytic effect of basic impurities is also observed in the H/D
conversion at C2 for 2. Screening with different added amounts of
1-MeIm at 311.90 K clearly illustrates the effect of the base on the
kinetics (Experiments 3-7, Table 1). The more base that is added,
the faster are the deuteration kinetics. The presence of 3 % of
stronger bases such as Et N and NaOD (40 wt.% solution) also
3
increase the deuterium labelling at C4 and C5 (Experiments 8-9,
Table 1).
functional,[
16]
Grimme's D3 dispersion correction,
[17]
RI
approximation[ and the def2-SVP basis sets), with varying
C2-H bond lengths, for [bmim]Cl and a cluster of 21 water
molecules. The maximum energy structure was stripped of the
chloride anion and all but 3 water molecules. A transition-state
search was performed using hybrid Hessian matrices. Full QM
Hessian matrices using the def2-TZVP basis sets[19] were then
calculated to confirm the nature of the equilibrium and transition-
18]
[19]
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Table 1. Kinetic data for the deuteration in experiments 1-2 (neutral conditions, excess of D
2
O), 3-9 (basic conditions), and 10-14 (acidic conditions), together with
the D incorporation.
mol% with respect to
the IL
D incorporation / %
Experiment
Conditions[a]
Ionic Liquid (IL)
Temperature / K
Time / h
C2
C4
C5
1
2
3
4
5
6
7
8
9
Pure D
Pure D
2
O
O
3
2
2
2
2
2
2
2
2
2
2
2
2
2
82
82
0.38
0.75
1
1.5
3
3
3
1
10
50
100
200
311.90
339.45
311.90
311.90
311.90
311.90
311.90
300.25
300.25
300.25
300.25
300.25
300.25
300.25
4.8
27
97
53
99
99
99
99
99
99
99
10
7
20
7
26
7
2
3.3[
b]
15
15
15
15
16
19
31
13
10
14
9
20
20
20
20
21
24
37
16
12
19
13
4
1-MeIm
1-MeIm
1-MeIm
1-MeIm
1-MeIm
[
b]
b]
b]
b]
b]
b]
0.85
0.57[
[
0.29
0.16[
0.16[
0.16[
192
3
Et N
NaOD (40 wt. %)
DCl (35 wt. %)
DCl (35 wt. %)
DCl (35 wt. %)
DCl (35 wt. %)
DCl (35 wt. %)
10
11
12
13
14
192
192
192
192
11
6
0
2
[
2
a] ionic liquid (0.370 – 0.424 mmol) in D O (34.4 mmol), [b] these time increments, corresponding to 99% conversion, were selected from the arrayed kinetic data.
The H/D exchange under neutral conditions mainly occurs at C2
while the deuterium incorporation at C4 and C5 is less significant,
while under basic conditions the deuteration is more effective for
all positions of the ring. However, in acidic environment
To put the results in context, the H/D exchange of imidazolium
ionic liquids is observed under neutral aqueous conditions via a
concerted ‘carbene-free’ transition-state involving proton-
deuteron exchange. The presence of additional explicit base is
shown to catalyse the reaction, which has implications for a wide
range of applied chemistries using technical purity ionic liquids.
Under neutral conditions, water is clearly also acting as both a
weak base and acid.
(
Experiments 10-14, Table 1) the D incorporation slows down
considerably and H/D exchange is even slightly preferential at C4
and C5, over C2. At elevated acid concentrations (Experiments
13-14) the H/D exchange is rather much slower. Again, this
confirms the effect that basicity has on the exchange kinetics.
Computational vs experimental activation energies are the same
magnitude, which gives very strong support for this alternative
mechanism, considering the presence of basic impurities has a
major catalytic effect on the exchange kinetics. This mechanism
is also confirmed by Gehrke and Hollóczki[13] who showed
computationally that the Gibbs free energy barriers for a series of
conjugation reactions, between aldehydes and NHC precursors,
all show lower energy barriers for the ‘carbene-free’ (associative)
vs ‘free-carbene’ (dissociative) mechanism. In addition, no
experimental evidence has yet been produced which has clearly
identified free carbene in ionic liquid solution.
Figure 4 illustrates the effect on H/D conversion of the counter
anion (chloride or acetate under neutral conditions) vs the
inclusion of 1-MeIm (explicit neutral base). These comparative
experiments were all recorded at 311.90 K. Kinetics for C2-H/D
exchange on 2, under neutral conditions, is clearly slowest by a
large margin. Conversion of the high purity chloride, 2, to high
purity acetate, 3, allows for a considerable rate increase, under
neutral conditions. However, the incorporation of 1-MeIm allows
for the most rapid kinetics, with 1.5 mol% affording almost
complete conversion near the start of the experiment time-frame.
The more rapid kinetics were also observed when a commercial
sample of 2 was used, without the addition of any base
Daud et al.[4b] have given tentative evidence for the spontaneous
formation of carbene (as a non-rate limiting step), in mixtures of
1-ethyl-3-methylimidazolium acetate ([emim][OAc]) and 1-ethyl-
2,3-dimethylimidazolium bistriflimide. This conclusion is based on
the lack of observation of a kinetic isotope effect when comparing
the kinetics of reaction of the C2 protonated vs the C2 deuterated
version of [emim][OAc], with anisaldehyde. However, it is not clear
how the kinetic isotope effect should affect the kinetics of the
concerted mechanisms proposed herein and in the Gehrke report.
Nevertheless, Arduengo[4f] and others[4] have clearly
demonstrated that the presence of strong enough bases does
allow for even isolation of imidazolium carbenes. Therefore, it
should be assumed that ‘free-carbene’ will form at some point and
is more a matter of equilibration, depending on the presence of
more or less unconjugated basic species (anions or impurities)
and temperature conditions.
(
supporting Information Figure S3). This indicates that the
presence of basic impurities in commercial ionic liquids may have
a huge impact on the validity of any chemistry performed within.
Based on these combined results, it is emphasised that the effect
of impurities on different chemistries should be tested, in
particular when technical purity ionic liquids are used. In regard to
biomass processing, which utilises the more basic ionic liquids,
Figure 4. Effect of different counter ions and basic impurities on the H/D
conversion at 311.90 K.
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COMMUNICATION
such as 1-ethyl-3-methylimidazolium acetate initial reports are
already appearing to show the influence of such impurities.[23]
However, in the past 2 has been widely used as an ionic liquid or
as one of the customary precursor to generate NHCs species. It
has been demonstrated that impurities may be more responsible
for chemistry than the anion choice, neglecting the effect of
physical properties.
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21]. The possibility of a sequential deuteration mechanism was also
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supporting information section 6e, page 6).
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Angewandte Chemie International Edition
10.1002/anie.201805016
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
DFT transition-state modelling yields
a ‘carbene-free’ mechanism for the
archetypical deuterium exchange at
C2 in imidazolium ionic liquids. This
was also confirmed through
Daniel Rico del Cerro*, Raúl Mera-
Adasme*, Alistair W.T. King, Jesus E.
Perea-Buceta, Sami Heikkinen, Tapio
Hase, Dage Sundholm*, Kristiina
Wähälä.
determination of an experimental
activation energy, almost identical to
the DFT result. Impurities in technical
ionic liquids are plainly implicated in
enhanced reactivity.
Page No. – Page No.
On the mechanism of the reactivity of
the 1,3-dialkylimidazolium salts
under basic to acidic conditions: a
combined kinetic and computational
study.
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